Defective mucus clearance or excess mucus production contribute to multiple respiratory disorders, including asthma and chronic obstructive pulmonary disease. In the airway, mucus is produced by club and goblet cells and transported by ciliated cells, all of which are present in the epithelium. During development, ligands of the Jagged family, JAG1 and JAG2, activate NOTCH signaling in adjacent cells to specify these cells. In experiments with adult mice, Lafkas et al. found that inhibition of JAG1 with an isoform-specific, function-blocking antibody decreased the number of club cells, while increasing the number of ciliated cells, without altering either cell death or cell proliferation. Blocking both JAG1 and JAG2 function with specific antibodies resulted in loss of nearly all club cells, except those at two sites, and an increase in the number of ciliated cells in the epithelium. Consistent with transdifferentiation of club cells into ciliated cells, JAG blockade induced the appearance of a small number of cells with markers of both club and ciliated cells, and lineage-tracing experiments with club cells confirmed that JAG inhibition promoted this transdifferentiation event. Exposure of the mice to function-blocking antibodies specific for the various NOTCH isoforms indicated that NOTCH2 was the main receptor responsible for the JAG1-mediated maintenance of club cells. In a mouse model of respiratory disease associated with excess mucus production, inhibition of JAG function, either JAG1 specifically or both JAG1 and JAG2, reduced goblet cell metaplasia when administered shortly after the inflammatory stimulus and reversed goblet cell metaplasia when administered more than a month after the inflammatory stimulus, when metaplasia was well established. JAG blockade did not alter the severity of inflammation or the infiltration of immune cells following the inflammatory stimulus, indicating that the effects were specific to the epithelium and not secondary to altered immune response. These results not only demonstrate plasticity in the cells of the adult airway, but suggest that selective JAG antagonism may be a specific therapeutic option in airway diseases associated with excess mucus production or defective clearance.